**2. Nutrients and energy sensors: importance in glucose and energy homeostasis**

Nutrient-sensing mechanisms are found in all organisms, from yeast through to mammals. Importantly, some of these mechanisms in multicellular organisms have also evolved for regulation by the endocrine system, allowing the coordination of nutrient-sensing activity among different cells/tissues in the body [2].

Nutrient sensors are proteins that detect fluctuations in nutrient levels or products of their metabolism within the physiological range, and induce a cellular response, leading to changes in the nutrient distribution or in feeding behavior [1]. These sensors respond to alterations in nutrient levels through diverse mechanisms, including the activation of phosphorylation cascades, changes in gene transcription, and enzymatic activities, among others [2].

The sensing of a nutrient may involve the direct binding of its molecule to the sensor or an indirect mechanism relying on the detection of a surrogate molecule that reflects nutrient abundance. There are homeostatic responses in multicellular eukaryotes to maintain nutrient levels circulating within a narrow range, such as hormone release, which act as signals to facilitate the coordination of consistent responses in the whole organism [3].

An effective and adequate response to changes in nutrient availability is vital in the human body, and its alteration triggers pathologies such as obesity, metabolic syndrome, and aging-related diseases (e.g. cancer and neurodegeneration).

Some situations in which nutrient sensors are chronically affected by excessive amounts of certain nutrients (e.g. carbohydrates and some fats) lead to the development of common characteristics of obesity and type 2 diabetes mellitus (T2D), such as insulin resistance, oxidative stress, and the dysfunction of organelles including the endoplasmic reticulum and mitochondria [4].

The increasing number of overweight and obese people, and associated diseases such as T2D, is driving research to explore the basic mechanisms that maintain nutrient homeostasis in a healthy state and the molecular mechanisms disrupted in T2D and obesity, as well as the neural and molecular underpinnings of feeding behavior. A central role in these disease-related mechanisms corresponds to nutrient sensing and the regulation of feeding behavior [1].

Glucose is a critical nutrient in mammals, with extracellular and intracellular mechanisms to maintain its levels within a narrow physiological band.

Glucose is an energy substrate, but it is also a key molecule in the control of glucosedependent insulin secretion by the pancreas. The increase in insulin in the blood as glycaemia facilitates the uptake of glucose by the liver and skeletal muscle, highlighting the cooperation and retro-regulation between glucose and insulin signaling. In short, circulating and intracellular glucose, acting as a signaling molecule, is detected by different glucose sensors that modulate eating behavior and the release of counterregulatory hormones in response to hypoglycemic states. The answer is therefore to maintain glucose and energy homeostasis [5], avoiding the development of T2D and other diseases. Some of the main nutrient sensors described are the following:

• **Glucokinase (GCK)**: It is an enzyme that catalyzes the phosphorylation of glucose to glucose-6-phosphate. GCK is expressed in hepatocytes, pancreatic α and β cells, entero-endocrine cells, and specialized brain cells in humans and most other vertebrates. It is considered a true glucose sensor due to its kinetic properties that ensure that the rate of glucose phosphorylation is proportional to blood glucose levels. For example, pancreatic GCK connects glucose sensing to insulin secretion by the pancreatic β-cell, and so regulates blood glucose homeostasis.

GCK in the liver is also a glucose sensor (**Figure 1**). Its activity regulates the rate of glycogen accumulation and hepatic glucose production [6]. Mutations in the GCK gene that increase enzyme activity lead to hypoglycemia due to hyperinsulinism, while mutations that decrease enzyme activity lead to hyperglycemia or diabetes. Due to its importance in glucose homeostasis, this enzyme is one of the main study targets for the development of a new antidiabetic therapy strategy [7].

**345**

*Role of Nutrient and Energy Sensors in the Development of Type 2 Diabetes*

Additionally, GCK is a key component in glucose-sensing neurons located in

*PASK signaling interaction with other nutrient sensors. PAS domains detect environmental parameters (light, oxygen and redox state). A metabolite or protein binds to the PAS domain after transient activation auto- or transphosphorylation stabilizes and activates PASK. Physiological effects of PASK in other nutrient sensors (glucose transporter (GLUT2), glucokinase (GCK), AMP-activated kinase (AMPK) and mammalian target of rapamycin (mTOR))/S6K pathway due to activation or inhibition (direct: solid lines; indirect: dashed* 

• **Glucose transporter GLUT-2**: It is a glucose transporter that acts as a sensor of changes in extracellular glucose levels. This is due to a high Km (more than other glucose transporters of the same family) and thus a very low affinity for glucose, allowing a rapid equilibrium between the glucose concentration on both sides of the membrane, independently of the action of insulin [11]. GLUT2 is expressed mainly in hepatic cells, pancreatic β cells, basolateral membranes of intestinal, renal epithelial cells, and in specific brain nuclei. In hepatic cells, GLUT2 involves an efficient transport of glucose across the plasmatic membrane only when intra- or extra-cellular glucose is high, being a key controller of glucose homeostasis (**Figure 1**). β-pancreatic cells take up glucose through the GLUT-2 transporter and carry out insulin synthesis and secretion. Glucose transport by GLUT-2 and then GCK facilitates oxidation by increasing intracellular ATP, which leads to signaling via ATP-dependent K<sup>+</sup> channels [1]. Decreased GLUT2 levels in pancreatic β cells have been detected

in cases of diabetes in both animals and human patients.

regions involved in controlling feeding behavior [9, 12, 13].

GLUT2 is also found in neurons located in certain glucose-sensing brain

• **AMP activated protein kinase (AMPK):** It is a heterotrimeric complex with a serine/threonine kinase domain [14, 15]. AMPK perceives cellular energy availability by detecting the AMP/ATP ratio (**Figure 1**). This kinase is activated in states of low energy availability or metabolic stress that reduces

*DOI: http://dx.doi.org/10.5772/intechopen.95454*

the hypothalamus [8–10].

**Figure 1.**

*lines).*

*Role of Nutrient and Energy Sensors in the Development of Type 2 Diabetes DOI: http://dx.doi.org/10.5772/intechopen.95454*

#### **Figure 1.**

*Type 2 Diabetes - From Pathophysiology to Cyber Systems*

and enzymatic activities, among others [2].

responses in the whole organism [3].

the endoplasmic reticulum and mitochondria [4].

sensing and the regulation of feeding behavior [1].

Nutrient sensors are proteins that detect fluctuations in nutrient levels or products of their metabolism within the physiological range, and induce a cellular response, leading to changes in the nutrient distribution or in feeding behavior [1]. These sensors respond to alterations in nutrient levels through diverse mechanisms, including the activation of phosphorylation cascades, changes in gene transcription,

The sensing of a nutrient may involve the direct binding of its molecule to the sensor or an indirect mechanism relying on the detection of a surrogate molecule that reflects nutrient abundance. There are homeostatic responses in multicellular eukaryotes to maintain nutrient levels circulating within a narrow range, such as hormone release, which act as signals to facilitate the coordination of consistent

An effective and adequate response to changes in nutrient availability is vital in the human body, and its alteration triggers pathologies such as obesity, metabolic syndrome, and aging-related diseases (e.g. cancer and neurodegeneration).

Some situations in which nutrient sensors are chronically affected by excessive amounts of certain nutrients (e.g. carbohydrates and some fats) lead to the development of common characteristics of obesity and type 2 diabetes mellitus (T2D), such as insulin resistance, oxidative stress, and the dysfunction of organelles including

The increasing number of overweight and obese people, and associated diseases

Glucose is a critical nutrient in mammals, with extracellular and intracellular

• **Glucokinase (GCK)**: It is an enzyme that catalyzes the phosphorylation of glucose to glucose-6-phosphate. GCK is expressed in hepatocytes, pancreatic α and β cells, entero-endocrine cells, and specialized brain cells in humans and most other vertebrates. It is considered a true glucose sensor due to its kinetic properties that ensure that the rate of glucose phosphorylation is proportional to blood glucose levels. For example, pancreatic GCK connects glucose sensing to insulin secretion by the pancreatic β-cell, and so regulates blood glucose

GCK in the liver is also a glucose sensor (**Figure 1**). Its activity regulates the

Mutations in the GCK gene that increase enzyme activity lead to hypoglycemia due to hyperinsulinism, while mutations that decrease enzyme activity lead to hyperglycemia or diabetes. Due to its importance in glucose homeostasis, this enzyme is one of the main study targets for the development of a new antidia-

rate of glycogen accumulation and hepatic glucose production [6].

Glucose is an energy substrate, but it is also a key molecule in the control of glucosedependent insulin secretion by the pancreas. The increase in insulin in the blood as glycaemia facilitates the uptake of glucose by the liver and skeletal muscle, highlighting the cooperation and retro-regulation between glucose and insulin signaling. In short, circulating and intracellular glucose, acting as a signaling molecule, is detected by different glucose sensors that modulate eating behavior and the release of counterregulatory hormones in response to hypoglycemic states. The answer is therefore to maintain glucose and energy homeostasis [5], avoiding the development of T2D and other diseases. Some of the main nutrient sensors described are the following:

such as T2D, is driving research to explore the basic mechanisms that maintain nutrient homeostasis in a healthy state and the molecular mechanisms disrupted in T2D and obesity, as well as the neural and molecular underpinnings of feeding behavior. A central role in these disease-related mechanisms corresponds to nutrient

mechanisms to maintain its levels within a narrow physiological band.

**344**

homeostasis.

betic therapy strategy [7].

*PASK signaling interaction with other nutrient sensors. PAS domains detect environmental parameters (light, oxygen and redox state). A metabolite or protein binds to the PAS domain after transient activation auto- or transphosphorylation stabilizes and activates PASK. Physiological effects of PASK in other nutrient sensors (glucose transporter (GLUT2), glucokinase (GCK), AMP-activated kinase (AMPK) and mammalian target of rapamycin (mTOR))/S6K pathway due to activation or inhibition (direct: solid lines; indirect: dashed lines).*

Additionally, GCK is a key component in glucose-sensing neurons located in the hypothalamus [8–10].


ATP production (e.g. heat shock, hypoxia, ischemia and fasting conditions) or accelerates its consumption (muscle contraction). Once active, AMPK acts by inhibiting the anabolic pathways responsible for the synthesis of macromolecules (proteins and glycogen) and lipids (fatty acids, triglycerides and cholesterol), and by activating catabolic pathways, such as the β-oxidation of fatty acids, glucose uptake and glycolysis. The net result of AMPK activity is the restoration of the energy balance, as the main energy sensor [16]. The AMPK pathway at central level integrates peripheral information through nutrients and hormones. Hypothalamic AMPK is involved in feeding behavior, the thermogenesis of brown adipose tissue (BAT) and browning of white adipose tissue (WAT) [17, 18].


This chapter will focus on the study of this last sensor, and like AMPK and mTORC1, it can be considered a pharmacological target for diseases, such as obesity and diabetes.

#### **2.1 Neuronal and peripheral regulation of homeostasis by nutrient sensing**

The key to maintaining homeostatic and energy control is a balanced food intake and energy expenditure, whereas altered regulation leads to obesity and T2D. The regulation of the energy balance is controlled by the hypothalamus, as the central organ that integrates nutrient levels and hormonal changes. The hypothalamic response to regulate glucose and whole-body energy homeostasis is to control food intake and several physiological functions in peripheral organs, such as lipid metabolism and thermogenesis [29, 30]. The brain receives inputs from nutrients, adiposity signals, and hormonal neural and metabolic signaling from the gastrointestinal tract. The gut-brain and gut-brain-liver axes act to regulate energy

**347**

*Role of Nutrient and Energy Sensors in the Development of Type 2 Diabetes*

and glucose homeostasis, respectively [31–33]. The brain likewise controls energyconsuming processes such as skeletal muscle fatty acid oxidation, thermogenesis, and locomotor activity [34]. Deficient intercommunications between the brain and peripheral organs may contribute to the appearance of obesity and T2D [30, 33]. The hypothalamus is a key brain area for maintaining an energy balance and homeostasis. Hypothalamic areas thereby play a key role in the control of food intake and energy homeostasis. The mid-20th century recorded the first indications that the electrical stimulation of the ventromedial hypothalamus (VMH) suppresses food intake, and that bilateral lesions of these areas induce hyperphagia and obesity. The VMH has therefore been called the satiety center. By contrast, alterations in the lateral hypothalamic area (LH) induce the opposite set of responses, and the LH is hence called the hunger center. Changes in blood glucose levels can be monitored by neuronal cells located in the hypothalamus or the brain stem [35]. They can therefore act as a true glucose sensor in the control of food intake and energy homeostasis. In fact, the first brain glucose sensors were discovered in the VMH and LH nucleus, where circulating glucose concentrations drive changes in neuronal electrical activity [36, 37]. This means glucose would act mainly as an excitatory molecule in certain VMH neurons, and as an inhibitory molecule in those of LH and the nucleus of the tractus solitarius (NTS) [38]. This is due to at least two kinds of glucose sensor neurons: glucose-excited neurons (GE) are located mainly in the VMH (as well as the arcuate nucleus, ARC, and the paraventricular nucleus PVN), and are excited by increased glucose levels in the extracellular space, while glucose-inhibited neurons (GI) are present mainly in the LH, median ARC, and PVN, and are excited by decreases in glucose concentrations [10, 37, 39]. It has been suggested that the activation of the firing rate of GE neurons depends on the closure

ATP channels by increases in extracellular glucose (similar

ATP channels and depolarization, promot-

/

electrophysiological pattern to β-pancreatic cells), whereas GI neurons may increase their firing rate in response to hypoglycemia following the inactivation of the Na+


Hypothalamic sensing neurons also use fatty acids (FA) as signaling molecules [46]. Some of these sensing neurons respond to both FA and glucose, whereby these neurons distinguish between fasting and feeding states. When the effect of glucose is excitatory, FA tend to inhibit those neurons [46]. A deficiency of fatty acid translocator/receptor CD36 in VMH neurons stimulates food intake, enhances insulin resistance, and increases body weight and fat mass in lean and obese rats [47]. FA sensing therefore plays a key role in integrating signals for regulating glucose and

It has also been reported that FA are oxidized by astrocytes in VMH under a low-fat diet, while under a high-fat diet (HFD) astrocytes in this area generate ketone bodies that can be exported to neurons and signal a decrease in short-term food intake and protect against obesity. However, this effect is lost when besides

*DOI: http://dx.doi.org/10.5772/intechopen.95454*

of the ATP-sensitive K<sup>+</sup>

leading to the closure of ATP-sensitive K+

energy homeostasis and fat deposition.

ing Ca2+ influx and neurotransmitter release [33, 44, 45].

K+

#### *Role of Nutrient and Energy Sensors in the Development of Type 2 Diabetes DOI: http://dx.doi.org/10.5772/intechopen.95454*

*Type 2 Diabetes - From Pathophysiology to Cyber Systems*

adipose tissue (WAT) [17, 18].

in the control of feeding behavior [22].

epigenetics and differentiation [28].

ATP production (e.g. heat shock, hypoxia, ischemia and fasting conditions) or accelerates its consumption (muscle contraction). Once active, AMPK acts by inhibiting the anabolic pathways responsible for the synthesis of macromolecules (proteins and glycogen) and lipids (fatty acids, triglycerides and cholesterol), and by activating catabolic pathways, such as the β-oxidation of fatty acids, glucose uptake and glycolysis. The net result of AMPK activity is the restoration of the energy balance, as the main energy sensor [16]. The AMPK pathway at central level integrates peripheral information through nutrients and hormones. Hypothalamic AMPK is involved in feeding behavior, the thermogenesis of brown adipose tissue (BAT) and browning of white

• **Mammalian Target of Rapamycin (mTOR)**: The mTORC1 complex is a serine/threonine kinase which forms part of the mTOR/S6K pathway integrating nutrients, hormones, growth factors and cellular energy levels to control protein transcription and synthesis and cell size, growth, metabolism, autophagy and thermogenesis [19]. Growth factors, amino acids, mitogens, and favorable energy states activate the mTORC1/S6K1 pathway, promoting anabolic processes (**Figure 1**), while states of energy depletion and cellular stress such as hypoxia suppress this pathway. The hypothalamic mTORC1 complex is an energy sensor involved in food intake and body weight control [20, 21]. AMPK and mTORC1 act together in food intake regulation, as low nutrient levels during fasting activate AMPK, although the mTORC1 complex remains inactive, while the activity of these sensors is reversed after food ingestion, indicating that AMPK and mTORC1 could have opposite functions

• **PAS kinase (PASK):** It is also called PASKIN, and is defined as the protein kinase that contains an N-terminal Per-Arnt-Sim (PAS) domain and a C-terminal serine/threonine kinase catalytic domain [23]. Like AMPK and mTORC1, it is a nutrient-responsive protein that regulates glucose metabolism and cellular energy, and is also responsive to a variety of intracellular cues, including light, oxygen, and redox state, among many others [24]. In mammals, PASK may be activated by small metabolites, and could regulate glycogen synthesis and protein translation (**Figure 1**), in addition to being involved in the regulation of glucose homeostasis and energy metabolism [25–27], and

This chapter will focus on the study of this last sensor, and like AMPK and mTORC1, it can be considered a pharmacological target for diseases, such as obesity

**2.1 Neuronal and peripheral regulation of homeostasis by nutrient sensing**

The key to maintaining homeostatic and energy control is a balanced food intake and energy expenditure, whereas altered regulation leads to obesity and T2D. The regulation of the energy balance is controlled by the hypothalamus, as the central organ that integrates nutrient levels and hormonal changes. The hypothalamic response to regulate glucose and whole-body energy homeostasis is to control food intake and several physiological functions in peripheral organs, such as lipid metabolism and thermogenesis [29, 30]. The brain receives inputs from nutrients, adiposity signals, and hormonal neural and metabolic signaling from the gastrointestinal tract. The gut-brain and gut-brain-liver axes act to regulate energy

**346**

and diabetes.

and glucose homeostasis, respectively [31–33]. The brain likewise controls energyconsuming processes such as skeletal muscle fatty acid oxidation, thermogenesis, and locomotor activity [34]. Deficient intercommunications between the brain and peripheral organs may contribute to the appearance of obesity and T2D [30, 33].

The hypothalamus is a key brain area for maintaining an energy balance and homeostasis. Hypothalamic areas thereby play a key role in the control of food intake and energy homeostasis. The mid-20th century recorded the first indications that the electrical stimulation of the ventromedial hypothalamus (VMH) suppresses food intake, and that bilateral lesions of these areas induce hyperphagia and obesity. The VMH has therefore been called the satiety center. By contrast, alterations in the lateral hypothalamic area (LH) induce the opposite set of responses, and the LH is hence called the hunger center. Changes in blood glucose levels can be monitored by neuronal cells located in the hypothalamus or the brain stem [35]. They can therefore act as a true glucose sensor in the control of food intake and energy homeostasis. In fact, the first brain glucose sensors were discovered in the VMH and LH nucleus, where circulating glucose concentrations drive changes in neuronal electrical activity [36, 37]. This means glucose would act mainly as an excitatory molecule in certain VMH neurons, and as an inhibitory molecule in those of LH and the nucleus of the tractus solitarius (NTS) [38]. This is due to at least two kinds of glucose sensor neurons: glucose-excited neurons (GE) are located mainly in the VMH (as well as the arcuate nucleus, ARC, and the paraventricular nucleus PVN), and are excited by increased glucose levels in the extracellular space, while glucose-inhibited neurons (GI) are present mainly in the LH, median ARC, and PVN, and are excited by decreases in glucose concentrations [10, 37, 39]. It has been suggested that the activation of the firing rate of GE neurons depends on the closure of the ATP-sensitive K<sup>+</sup> ATP channels by increases in extracellular glucose (similar electrophysiological pattern to β-pancreatic cells), whereas GI neurons may increase their firing rate in response to hypoglycemia following the inactivation of the Na+ / K+ -ATPase pump (similar electrophysiological pattern to α-pancreatic cells) [40].

Some of the component molecules responsible for the hypothalamic glucose sensing systems are as follows: GCK, GLUT-2, and the GLP-1 receptor, which are co-expressed in areas involved in energy homeostasis regulation, food intake, and glucose metabolism [9, 12, 41, 42]. The most glucose-sensitive regulator seems to be the GCK, which is present in both GE and GI neurons (albeit to a lesser extent) [43]. However, glucose transporters such as GLUT-2, GLUT-3, the insulin-dependent transporter (GLUT-4), and the sodium-glucose transporter (SGLT) do not seem to have a predominant role in the response by GE and GI neurons to alterations in glucose levels [10]. GE neurons are known to use GLUT-2 for glucose uptake, then GCK mediates the phosphorylation, and the glucose oxidation increases ATP/ADP, leading to the closure of ATP-sensitive K+ ATP channels and depolarization, promoting Ca2+ influx and neurotransmitter release [33, 44, 45].

Hypothalamic sensing neurons also use fatty acids (FA) as signaling molecules [46]. Some of these sensing neurons respond to both FA and glucose, whereby these neurons distinguish between fasting and feeding states. When the effect of glucose is excitatory, FA tend to inhibit those neurons [46]. A deficiency of fatty acid translocator/receptor CD36 in VMH neurons stimulates food intake, enhances insulin resistance, and increases body weight and fat mass in lean and obese rats [47]. FA sensing therefore plays a key role in integrating signals for regulating glucose and energy homeostasis and fat deposition.

It has also been reported that FA are oxidized by astrocytes in VMH under a low-fat diet, while under a high-fat diet (HFD) astrocytes in this area generate ketone bodies that can be exported to neurons and signal a decrease in short-term food intake and protect against obesity. However, this effect is lost when besides

HFD there is a resistance to leptin. Animals in these cases remain hyperphagic and exposed to obesity [48].

Additionally, with changes in nutrient concentrations some neurons located in hypothalamic nuclei secrete and respond to the hormones and neuropeptides involved in the control of food intake and energy homeostasis.

For example, the ARC secretes hormones and detects inputs from the peripheral signals involved in the control of feeding behavior. There are two important subpopulations of secretory neurons in ARC: one synthetizes the α-melanocytestimulating hormone (α-MSH) derived from pro-opiomelanocortin (POMC), as well as the cocaine- and amphetamine-regulated transcript (CART); both of which are anorexigenic peptides. The second subpopulation of neurons secretes the agouti-related protein (AgRP) and neuropeptide Y (NPY) orexigenic peptides [49]. These peptides are directed by nerve fibers to other important hypothalamic regions, and their synthesis and release coordinate with metabolic sensors to accurately control eating behavior and energy metabolism. Additionally, these two populations and other neurons located in different hypothalamic nuclei have receptors for hormones secreted peripherally, such as leptin, insulin, ghrelin, and other gastrointestinal peptides, such as glucagon like peptide (GLP-1), which in turn are being secreted under the control of changes in nutrient availability.

AMPK is another hypothalamic molecule responsible for energy sensing. It has been reported to act as an "energy integrator", and not only perceives the cellular energy state, but also has a role in the regulatory mechanisms of body energy homeostasis [50, 51]. It has a mainly neuronal distribution [52], highly expressed in ARC, PVN, VMH and LH, with AMPKα2 being the most predominant isoform [53].

Fasting increases and feeding decreases AMPK activity in various hypothalamic nuclei [18, 53]. Several studies have shown that hypothalamic AMPK is regulated by blood glucose levels. Peripheral or central hyperglycemia inhibits AMPK in several hypothalamic nuclei. Furthermore, the anorexigenic neuronal signaling (NPY/ AgRP) is AMPK-dependent in the hypothalamus. Thus, AMPK mutants have suppressed the NPY/AgRP response, and therefore food intake, reducing body weight. However, elevated AMPK increases NPY/AgRP expression, food intake and body weight [53, 54].

Fasting and feeding are accompanied by hormonal and nutrient changes both in peripheral tissues and in the CNS, which can lead to variations in AMPK activity. Accordingly, AMPK integrates nutritional information and hormonal signals. Several studies have shown that fasting and orexigenic signals (e.g. ghrelin, adiponectin, cannabinoids and glucocorticoids) increase hypothalamic AMPK activity, contributing to an increase in food intake; by contrast, food and anorectic signals such as leptin, insulin, resistin, GLP-1 and α-MSH decrease this kinase's activity, helping to generate a state of satiety. AMPK activation therefore promotes food intake, while the decrease in its enzymatic activity is associated with hypophagia. This effect is due, at least in part, to an increase in the expression of NPY and AgRP in the arcuate nucleus, and of MCH in the lateral hypothalamus [17, 18, 54].

AMPK activity can induce appetite via the inhibition of malonyl-CoA and the activation of carnitine palmitoyltransferase-1 (CPT-1). The inhibition of malonyl-CoA leads to decreased fatty acid synthesis and increased -oxidation. Furthermore, increased -oxidation could induce orexigenic gene expression. In addition, AMPK activation through the sympathetic nerve can reduce thermogenesis and energy expenditure. Additionally, activated hypothalamic AMPK may prompt enhanced glucose production [55].

Besides AMPK, mTORC1 is another hypothalamic metabolic sensor regulator of feeding behavior and body weight [20]. mTORC1 and the downstream target S6K1 are widely distributed in the brain, mainly in the PVN and ARC. Their signaling

**349**

*Role of Nutrient and Energy Sensors in the Development of Type 2 Diabetes*

responds to nutrient availability and is colocalized with NPY/AgRP and POMC/ CART neurons in the ARC [20]. mTORC1 activation decreases food intake and body weight [56]. mTORC1 integrates signals from nutrients, adiposity signals, and gut hormones [21]. Hypothalamic AMPK and mTORC1 respond to nutrient levels in opposite ways [57, 58]. Additionally, mTORC1 is inhibited by AMPK activation via the tuberous sclerosis complex 2 (TSC2) [59, 60]. Moreover, AMPK is also a substrate

In short, the interplay between both hypothalamic pathways plays an important

Several peripheral signals are involved in controlling food intake and energy homeostasis. Moreover, changes in nutrient levels involving glucose [61] and FA [62, 63] or ketone bodies [48], adiposity signals (leptin, insulin) [64], and gastrointestinal (ghrelin [65], GLP-1 [57, 58, 66]) signals, alter the activity of sensing

Two peripheral hormones, leptin and insulin, provide the brain with information about the energy stored as adipose tissue [64]. Leptin and insulin levels in plasma correlate with adipose mass and body weight. Insulin levels correlate better with visceral adiposity [67]. Its plasma levels also reflect changes, decreasing during fasting and increasing during feeding; glucose-induced insulin secretion is also dependent on body fat (review by Benoit et al.) [64]. Obesity is frequently related to insulin resistance as higher insulin levels are required to maintain suitable levels of blood glucose. The administration of insulin to the brain reduces food intake and increases energy expenditure [68]. Impaired insulin signaling due to neuronal deletion of the insulin receptor and insulin receptor substrate 2 (IRS2) increases food intake [69]. Leptin is secreted by adipose tissue, and blood levels correlate directly with adiposity [70]. Leptin receptor deficiency has been related to hyperphagia and obesity [71]. However, leptin supplied to the ARC reduces food intake and body

Hormones secreted in the gut after feeding as cholecystokinin and GLP-1 promote satiety when administered centrally and peripherally [66]. By contrast, ghrelin released under fasting conditions by the stomach acts as an orexigenic signal

The liver plays a vital role in regulating whole-body glucose and lipid homeostasis. It is the main site for the synthesis, metabolism, storage and redistribution of carbohydrates, proteins and lipids, especially during the adjustment periods in fasting and feeding. In postprandial states, the liver is exposed to more ingested nutrients and to higher levels than other tissues. The liver is especially responsible for much of glucose uptake when hyperinsulinemia and hyperglycemia coincide, storing it as a glycogen and associated to a reduction in muscle glucose uptake [73]. The efficiency of hepatic glucose uptake is coordinated neurally, depending also on diet components and high-fat and high-fructose decreases in glycogen storage. Glucose transport is facilitated by GLUT2, with the intrahepatic glucose concentration being similar to that of blood glucose. Its metabolism therefore depends on GCK activity, which in part determines glycogen synthesis [74]. By contrast, when blood glucose drops, and other organs require energy, the liver produces glucose by glycogenolysis and/or gluconeogenesis. Gluconeogenesis is responsible for half of the total glucose produced by the liver during an overnight fast, so this contribution is essential for glucose homeostasis [75]. Therefore, hepatic metabolism is critical for proper glucose homeostasis in response to insulin and for preventing diabetes [73, 75]. Insulin in the hypothalamic nuclei regulates hepatic glucose production [76, 77]. Insulin acts on the brain (hypothalamus and brain stem), also modulating pancreatic insulin and glucagon secretion [78]. The close coordination between the brain and peripheral

organs helps to maintain whole-body glucose and energy homeostasis.

*DOI: http://dx.doi.org/10.5772/intechopen.95454*

for the mTOR-S6K1 pathway (**Figure 1**) [22].

role in regulating food intake and body weight.

neurons located in the VMH and other brain areas.

weight, and promotes locomotor activity [72].

inducing food intake [31].

#### *Role of Nutrient and Energy Sensors in the Development of Type 2 Diabetes DOI: http://dx.doi.org/10.5772/intechopen.95454*

*Type 2 Diabetes - From Pathophysiology to Cyber Systems*

involved in the control of food intake and energy homeostasis.

being secreted under the control of changes in nutrient availability.

exposed to obesity [48].

HFD there is a resistance to leptin. Animals in these cases remain hyperphagic and

Additionally, with changes in nutrient concentrations some neurons located in hypothalamic nuclei secrete and respond to the hormones and neuropeptides

For example, the ARC secretes hormones and detects inputs from the peripheral signals involved in the control of feeding behavior. There are two important subpopulations of secretory neurons in ARC: one synthetizes the α-melanocytestimulating hormone (α-MSH) derived from pro-opiomelanocortin (POMC), as well as the cocaine- and amphetamine-regulated transcript (CART); both of which are anorexigenic peptides. The second subpopulation of neurons secretes the agouti-related protein (AgRP) and neuropeptide Y (NPY) orexigenic peptides [49]. These peptides are directed by nerve fibers to other important hypothalamic regions, and their synthesis and release coordinate with metabolic sensors to accurately control eating behavior and energy metabolism. Additionally, these two populations and other neurons located in different hypothalamic nuclei have receptors for hormones secreted peripherally, such as leptin, insulin, ghrelin, and other gastrointestinal peptides, such as glucagon like peptide (GLP-1), which in turn are

AMPK is another hypothalamic molecule responsible for energy sensing. It has been reported to act as an "energy integrator", and not only perceives the cellular energy state, but also has a role in the regulatory mechanisms of body energy homeostasis [50, 51]. It has a mainly neuronal distribution [52], highly expressed in ARC, PVN, VMH and LH, with AMPKα2 being the most predominant isoform [53]. Fasting increases and feeding decreases AMPK activity in various hypothalamic nuclei [18, 53]. Several studies have shown that hypothalamic AMPK is regulated by blood glucose levels. Peripheral or central hyperglycemia inhibits AMPK in several hypothalamic nuclei. Furthermore, the anorexigenic neuronal signaling (NPY/ AgRP) is AMPK-dependent in the hypothalamus. Thus, AMPK mutants have suppressed the NPY/AgRP response, and therefore food intake, reducing body weight. However, elevated AMPK increases NPY/AgRP expression, food intake and body

Fasting and feeding are accompanied by hormonal and nutrient changes both in peripheral tissues and in the CNS, which can lead to variations in AMPK activity. Accordingly, AMPK integrates nutritional information and hormonal signals. Several studies have shown that fasting and orexigenic signals (e.g. ghrelin, adiponectin, cannabinoids and glucocorticoids) increase hypothalamic AMPK activity, contributing to an increase in food intake; by contrast, food and anorectic signals such as leptin, insulin, resistin, GLP-1 and α-MSH decrease this kinase's activity, helping to generate a state of satiety. AMPK activation therefore promotes food intake, while the decrease in its enzymatic activity is associated with hypophagia. This effect is due, at least in part, to an increase in the expression of NPY and AgRP in the arcuate nucleus, and of MCH in the lateral hypothalamus [17, 18, 54]. AMPK activity can induce appetite via the inhibition of malonyl-CoA and the activation of carnitine palmitoyltransferase-1 (CPT-1). The inhibition of malonyl-CoA leads to decreased fatty acid synthesis and increased -oxidation. Furthermore, increased -oxidation could induce orexigenic gene expression. In addition, AMPK activation through the sympathetic nerve can reduce thermogenesis and energy expenditure. Additionally, activated hypothalamic AMPK may

Besides AMPK, mTORC1 is another hypothalamic metabolic sensor regulator of feeding behavior and body weight [20]. mTORC1 and the downstream target S6K1 are widely distributed in the brain, mainly in the PVN and ARC. Their signaling

**348**

prompt enhanced glucose production [55].

weight [53, 54].

responds to nutrient availability and is colocalized with NPY/AgRP and POMC/ CART neurons in the ARC [20]. mTORC1 activation decreases food intake and body weight [56]. mTORC1 integrates signals from nutrients, adiposity signals, and gut hormones [21]. Hypothalamic AMPK and mTORC1 respond to nutrient levels in opposite ways [57, 58]. Additionally, mTORC1 is inhibited by AMPK activation via the tuberous sclerosis complex 2 (TSC2) [59, 60]. Moreover, AMPK is also a substrate for the mTOR-S6K1 pathway (**Figure 1**) [22].

In short, the interplay between both hypothalamic pathways plays an important role in regulating food intake and body weight.

Several peripheral signals are involved in controlling food intake and energy homeostasis. Moreover, changes in nutrient levels involving glucose [61] and FA [62, 63] or ketone bodies [48], adiposity signals (leptin, insulin) [64], and gastrointestinal (ghrelin [65], GLP-1 [57, 58, 66]) signals, alter the activity of sensing neurons located in the VMH and other brain areas.

Two peripheral hormones, leptin and insulin, provide the brain with information about the energy stored as adipose tissue [64]. Leptin and insulin levels in plasma correlate with adipose mass and body weight. Insulin levels correlate better with visceral adiposity [67]. Its plasma levels also reflect changes, decreasing during fasting and increasing during feeding; glucose-induced insulin secretion is also dependent on body fat (review by Benoit et al.) [64]. Obesity is frequently related to insulin resistance as higher insulin levels are required to maintain suitable levels of blood glucose. The administration of insulin to the brain reduces food intake and increases energy expenditure [68]. Impaired insulin signaling due to neuronal deletion of the insulin receptor and insulin receptor substrate 2 (IRS2) increases food intake [69]. Leptin is secreted by adipose tissue, and blood levels correlate directly with adiposity [70]. Leptin receptor deficiency has been related to hyperphagia and obesity [71]. However, leptin supplied to the ARC reduces food intake and body weight, and promotes locomotor activity [72].

Hormones secreted in the gut after feeding as cholecystokinin and GLP-1 promote satiety when administered centrally and peripherally [66]. By contrast, ghrelin released under fasting conditions by the stomach acts as an orexigenic signal inducing food intake [31].

The liver plays a vital role in regulating whole-body glucose and lipid homeostasis. It is the main site for the synthesis, metabolism, storage and redistribution of carbohydrates, proteins and lipids, especially during the adjustment periods in fasting and feeding. In postprandial states, the liver is exposed to more ingested nutrients and to higher levels than other tissues. The liver is especially responsible for much of glucose uptake when hyperinsulinemia and hyperglycemia coincide, storing it as a glycogen and associated to a reduction in muscle glucose uptake [73]. The efficiency of hepatic glucose uptake is coordinated neurally, depending also on diet components and high-fat and high-fructose decreases in glycogen storage. Glucose transport is facilitated by GLUT2, with the intrahepatic glucose concentration being similar to that of blood glucose. Its metabolism therefore depends on GCK activity, which in part determines glycogen synthesis [74]. By contrast, when blood glucose drops, and other organs require energy, the liver produces glucose by glycogenolysis and/or gluconeogenesis. Gluconeogenesis is responsible for half of the total glucose produced by the liver during an overnight fast, so this contribution is essential for glucose homeostasis [75]. Therefore, hepatic metabolism is critical for proper glucose homeostasis in response to insulin and for preventing diabetes [73, 75]. Insulin in the hypothalamic nuclei regulates hepatic glucose production [76, 77]. Insulin acts on the brain (hypothalamus and brain stem), also modulating pancreatic insulin and glucagon secretion [78]. The close coordination between the brain and peripheral organs helps to maintain whole-body glucose and energy homeostasis.

In turn, there is a close relationship between the appearance of insulin resistance in the liver and the development of T2D [79, 80]. Decreased hepatic insulin sensitivity contributes to postprandial hyperglycemia and enhances hepatic glucose production, leading to exacerbated hyperglycemia and chronic hyperinsulinemia in diabetics [81]. There is evidence to suggest that impairing insulin hypothalamic signaling [82] or an HFD [83] contributes to the appearance of diabetes.

## **3. PASK: a new nutrient sensor**

PASK is an evolutionarily conserved nutrient-responsive protein kinase that regulates glucose homeostasis, senses a cell's energy or nutrient status, and suitably regulates cellular metabolism. PASK responds to glucose availability and regulates glucose homeostasis in yeast, rodents and mammals. Despite this pivotal role, the molecular mechanisms of PASK regulation and function are largely unknown [84].

PAS domains (see Section 2) are versatile sensors designed to detect environmental parameters, such as light, oxygen and redox state [24]. These domains are often regulated by the binding of a diverse group of small ligands, including ATP, heme or flavins, within the hydrophobic pocket at the core of the domain (review by Henry et al.) [85]. As with other PAS domains, the PASK adopts this characteristic fold and binds small organic molecules within its hydrophobic core [86]. Unlike other PAS domains, however, the physiological ligand(s) for PASK remain unknown. *In vitro* experiments performed indicate that this domain should inhibit kinase activity [84].

In a hypothetical activation model, a metabolite or protein activates PASK by binding to the PAS domain and relieving PAS domain inhibition. This transient activation may subsequently be stabilized through auto- or transphosphorylation (**Figure 1**). PASK can then phosphorylate several substrates (**Figure 2**) [23, 27, 86, 87].

PASK is known to be a physiological regulator of glucose metabolism, functioning in pancreatic islet cells regulating glucagon and insulin secretion [88, 89]; several translation factors and glycogen synthase are PASK substrates [90, 91], suggesting its implication in the control of protein synthesis and glycogen metabolism.

#### **Figure 2.**

*PAS Kinase substrates in mammals. Cellular process regulated by PAS kinase and* in vitro *or* in vivo *substrates identified in mammals. Glycogen metabolism: Glycogen synthase (GYS), Glycogen synthase kinase 3 beta (GSK3*β*). Protein translation: Alanine-tRNA ligase (AlaRS); Basic transcription factor 3 (BTF3); Eukaryotic translation elongation factor (eIF1A); Ribosomal proteins S2, S3A, S6, S8, S10 and S14 (RPS2), (RPS3A), (RPS6), (RPS8), (RPS10) and (RPS14). Gene expression: Histone H3 tails residues threonine 3, 6, 11 and serine 10 (H3T3), (H3T6), (H3T11) and (H3S10); Cell differentiation: WD repeat-containing protein 5 (WDR5) and Pancreatic Duodenal Homeobox 1 (PDX1).*

**351**

*Role of Nutrient and Energy Sensors in the Development of Type 2 Diabetes*

PASK has been reported to regulate many of the phenotypes.

been confirmed using PASK pharmacologic inhibitors [98].

(Veterinary Department of the canton of Zurich).

committed myoblasts (early stage of myogenesis) [100].

transcriptional activation.

Katschinski et al. [92] have been the first to inactivate mouse gene coding to PASK. These PASK-deficient mice (PASK−/−) recorded normal development, growth and reproduction. It was subsequently found that PASK−/− male mice are resistant to weight gain, hepatic triglyceride accumulation, and insulin resistance when placed on an HFD [93]. Without a change in food intake or exercise, these PASK−/− male mice also record a hypermetabolic phenotype, giving off more CO2 and taking in more O2. PASK is involved in the proteolytic maturation of the sterol regulatory binding protein (SREBP1c), the main lipogenic transcription factor [94, 95]. SREBP1c activity and target genes decreased in PASK−/− mice, with an associated

Lipids are important substances that store energy for oxidation and metabolism. As the main cause of imbalanced lipid metabolism, excessive lipid accumulation in the liver has been involved in the development of metabolic syndromes, such as T2D, obesity, hepatic adipose infiltration and unpredicted morbidity. It is therefore extremely important to maintain a balance between lipid synthesis and catabolism.

PASK deficiency decreases insulin production, insulin resistance, body weight and hepatic triglyceride accumulation, while leading to increased glycogen storage, as well as metabolic rate [97]. Some of the effects observed in PASK−/− have also

Our studies have been based on this mouse model. PASK−/− mice have been described by Hao et al. [93], and generously donated to us by Dr. Roland H. Wegner

New PASK functions have recently been described, including the unexpected role it has in promoting the differentiation of myogenic progenitor cells, embryonic stem cells, and adipogenic progenitor cells. This PASK function is dependent upon its ability to phosphorylate WD repeat-containing protein 5 (WDR5), which is a member of several protein complexes, including those that catalyze histone H3 Lysine 4 trimethylation (H3K4me3) during transcriptional activation. Thus, as an upstream kinase of WDR5, PASK integrates signaling cues with the transcriptional network to regulate the differentiation of progenitor cells [99]. In addition, the phosphorylation of PASK by mTORC1 is required for the activation of myogenin transcription, exiting from self-renewal, and the induction of the myogenesis program. mTORC1-PASK signaling is required for increasing myogenin-positive

Moreover, it has been confirmed that the metabolic sensor PASK could affect both the phosphorylation and the methylation of histone H3 tails. It contributes to the methylation of H3 lysine 4 (H3K4) di- and tri-methylation through its association with the H3K4 MLL2 methyltransferase complex and to the phosphorylation of several threonine residues (T3, T6 and T11) and serine (S10) on H3 as a histone kinase [101]. The methylation of histone H3 lysine 4 H3K4 has been linked to

**4. PASK hypothalamic function in food intake and energy homeostasis**

The hypothalamus is the key to controlling food intake. The identification of hypothalamic glucose sensing systems and neuronal populations expressing and responding to orexigenic and anorexigenic peptides (see Section 2.1) has focused the studies on the hypothalamic nuclei. They have been specifically directed toward identifying the mechanisms involved in controlling nutrient sensing, feeding behavior and its relationship with insulin actions in the central nervous system in order to regulate energy and glucose homeostasis. Hypothalamic metabolic sensors

*DOI: http://dx.doi.org/10.5772/intechopen.95454*

decrease in hepatic lipid deposits [96].

#### *Role of Nutrient and Energy Sensors in the Development of Type 2 Diabetes DOI: http://dx.doi.org/10.5772/intechopen.95454*

*Type 2 Diabetes - From Pathophysiology to Cyber Systems*

**3. PASK: a new nutrient sensor**

kinase activity [84].

In turn, there is a close relationship between the appearance of insulin resistance in the liver and the development of T2D [79, 80]. Decreased hepatic insulin sensitivity contributes to postprandial hyperglycemia and enhances hepatic glucose production, leading to exacerbated hyperglycemia and chronic hyperinsulinemia in diabetics [81]. There is evidence to suggest that impairing insulin hypothalamic

PASK is an evolutionarily conserved nutrient-responsive protein kinase that regulates glucose homeostasis, senses a cell's energy or nutrient status, and suitably regulates cellular metabolism. PASK responds to glucose availability and regulates glucose homeostasis in yeast, rodents and mammals. Despite this pivotal role, the molecular mechanisms of PASK regulation and function are largely unknown [84]. PAS domains (see Section 2) are versatile sensors designed to detect environmental parameters, such as light, oxygen and redox state [24]. These domains are often regulated by the binding of a diverse group of small ligands, including ATP, heme or flavins, within the hydrophobic pocket at the core of the domain (review by Henry et al.) [85]. As with other PAS domains, the PASK adopts this characteristic fold and binds small organic molecules within its hydrophobic core [86]. Unlike other PAS domains, however, the physiological ligand(s) for PASK remain unknown. *In vitro* experiments performed indicate that this domain should inhibit

In a hypothetical activation model, a metabolite or protein activates PASK by binding to the PAS domain and relieving PAS domain inhibition. This transient activation may subsequently be stabilized through auto- or transphosphorylation (**Figure 1**).

PASK is known to be a physiological regulator of glucose metabolism, function-

*PAS Kinase substrates in mammals. Cellular process regulated by PAS kinase and* in vitro *or* in vivo *substrates identified in mammals. Glycogen metabolism: Glycogen synthase (GYS), Glycogen synthase kinase 3 beta (GSK3*β*). Protein translation: Alanine-tRNA ligase (AlaRS); Basic transcription factor 3 (BTF3); Eukaryotic translation elongation factor (eIF1A); Ribosomal proteins S2, S3A, S6, S8, S10 and S14 (RPS2), (RPS3A), (RPS6), (RPS8), (RPS10) and (RPS14). Gene expression: Histone H3 tails residues threonine 3, 6, 11 and serine 10 (H3T3), (H3T6), (H3T11) and (H3S10); Cell differentiation: WD repeat-containing protein 5* 

PASK can then phosphorylate several substrates (**Figure 2**) [23, 27, 86, 87].

ing in pancreatic islet cells regulating glucagon and insulin secretion [88, 89]; several translation factors and glycogen synthase are PASK substrates [90, 91], suggesting its implication in the control of protein synthesis and glycogen metabolism.

signaling [82] or an HFD [83] contributes to the appearance of diabetes.

**350**

**Figure 2.**

*(WDR5) and Pancreatic Duodenal Homeobox 1 (PDX1).*

Katschinski et al. [92] have been the first to inactivate mouse gene coding to PASK. These PASK-deficient mice (PASK−/−) recorded normal development, growth and reproduction. It was subsequently found that PASK−/− male mice are resistant to weight gain, hepatic triglyceride accumulation, and insulin resistance when placed on an HFD [93]. Without a change in food intake or exercise, these PASK−/− male mice also record a hypermetabolic phenotype, giving off more CO2 and taking in more O2. PASK is involved in the proteolytic maturation of the sterol regulatory binding protein (SREBP1c), the main lipogenic transcription factor [94, 95]. SREBP1c activity and target genes decreased in PASK−/− mice, with an associated decrease in hepatic lipid deposits [96].

Lipids are important substances that store energy for oxidation and metabolism. As the main cause of imbalanced lipid metabolism, excessive lipid accumulation in the liver has been involved in the development of metabolic syndromes, such as T2D, obesity, hepatic adipose infiltration and unpredicted morbidity. It is therefore extremely important to maintain a balance between lipid synthesis and catabolism. PASK has been reported to regulate many of the phenotypes.

PASK deficiency decreases insulin production, insulin resistance, body weight and hepatic triglyceride accumulation, while leading to increased glycogen storage, as well as metabolic rate [97]. Some of the effects observed in PASK−/− have also been confirmed using PASK pharmacologic inhibitors [98].

Our studies have been based on this mouse model. PASK−/− mice have been described by Hao et al. [93], and generously donated to us by Dr. Roland H. Wegner (Veterinary Department of the canton of Zurich).

New PASK functions have recently been described, including the unexpected role it has in promoting the differentiation of myogenic progenitor cells, embryonic stem cells, and adipogenic progenitor cells. This PASK function is dependent upon its ability to phosphorylate WD repeat-containing protein 5 (WDR5), which is a member of several protein complexes, including those that catalyze histone H3 Lysine 4 trimethylation (H3K4me3) during transcriptional activation. Thus, as an upstream kinase of WDR5, PASK integrates signaling cues with the transcriptional network to regulate the differentiation of progenitor cells [99]. In addition, the phosphorylation of PASK by mTORC1 is required for the activation of myogenin transcription, exiting from self-renewal, and the induction of the myogenesis program. mTORC1-PASK signaling is required for increasing myogenin-positive committed myoblasts (early stage of myogenesis) [100].

Moreover, it has been confirmed that the metabolic sensor PASK could affect both the phosphorylation and the methylation of histone H3 tails. It contributes to the methylation of H3 lysine 4 (H3K4) di- and tri-methylation through its association with the H3K4 MLL2 methyltransferase complex and to the phosphorylation of several threonine residues (T3, T6 and T11) and serine (S10) on H3 as a histone kinase [101]. The methylation of histone H3 lysine 4 H3K4 has been linked to transcriptional activation.
